Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary... Show moreVascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-a, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p <0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy. Show less
Background and aims: There is some evidence of the implications of wall shear stress (WSS) derived from three-dimensional quantitative coronary angiography (3D-QCA) models in predicting adverse... Show moreBackground and aims: There is some evidence of the implications of wall shear stress (WSS) derived from three-dimensional quantitative coronary angiography (3D-QCA) models in predicting adverse cardiovascular events. This study investigates the efficacy of 3D-QCA-derived WSS in detecting lesions with a borderline negative fractional flow reserve (FFR: 0.81-0.85) that progressed and caused events.Methods: In this retrospective cohort study, we identified 548 patients who had at least one lesion with an FFR 0.81-0.85 and complete follow-up data; 293 lesions (286 patients) with suitable angiographic characteristics were reconstructed using a dedicated 3D-QCA software and included in the analysis. In the reconstructed models blood flow simulation was performed and the value of 3D-QCA variables and WSS distribution in predicting events was examined. The primary endpoint of the study was the composite of cardiac death, target lesion related myocardial infarction or clinically indicated target lesion revascularization.Results: During a median follow-up of 49.4 months, 37 events were reported. Culprit lesions had a greater area stenosis [(AS), 66.1% (59.5-72.3) vs 54.8% (46.5-63.2), p<0.001], smaller minimum lumen area [(MLA), 1.66 mm(2) (1.45-2.30) vs 2.10 mm(2) (1.69-2.70), p=0.011] and higher maximum WSS [9.0 Pa (5.10-12.46) vs 5.0 Pa (3.37-7.54), p < 0.001] than those that remained quiescent. In multivariable analysis, AS [hazard ratio (HR): 1.06, 95% confidence interval (CI): 1.03-1.10, p=0.001] and maximum WSS (HR: 1.08, 95% CI: 1.02-1.14, p=0.012) were the only independent predictors of the primary endpoint. Lesions with an increased AS (>= 58.6%) that were exposed to high WSS (>= 7.69Pa) were more likely to progress and cause events (27.8%) than those with a low AS exposed to high WSS (7.4%) or those exposed to low WSS that had increased (12.8%) or low AS (2.7%, p<0.001).Conclusions: This study for the first time highlights the potential value of 3D-QCA-derived WSS in detecting, among lesions with a borderline negative FFR, those that cause cardiovascular events. Show less
In recent years, the study of endothelial cell (EC) metabolism has led to the discovery of novel regulatory mechanisms and potential new targets for vascular-related diseases. Despite the fact that... Show moreIn recent years, the study of endothelial cell (EC) metabolism has led to the discovery of novel regulatory mechanisms and potential new targets for vascular-related diseases. Despite the fact that ECs have readily available oxygen in the blood, they mainly generate ATP via anaerobic glycolysis rather than Krebs cycle. In the context of atherosclerosis, there has been growing interest in understanding how EC metabolism affects plaque formation and intraplaque (IP) angiogenesis, which has been identified as a contributing factor for plaque vulnerability in human atherosclerosis.Among the enzymes involved in glycolytic flux modulation, PFKFB3 plays a critical role for the proliferation and migration of ECs. PFKFB3 is upregulated in atheroprone regions of arterial vessels and in carotid plaques of patients with elevated levels of lipoprotein(a). The experimental work of this thesis focuses on PFKFB3 as a modulator of EC glycolysis and its effects on atherosclerosis progression and IP angiogenesis.In the first part of this thesis, a pharmacological study with partial glycolysis inhibitor 3PO in the context of advanced atherosclerotic plaques is described. 3PO treatment restrains IP angiogenesis and plaque frequency but it does not affect plaque size and composition in ApoE-/-Fbn1C1039G+/- mice. In addition, a 3PO-mediated reduction in plaque formation is also observed in ApoE-/- mice that develop plaques without IP neovascularization.Furthermore, EC-specific PFKFB3 deletion leads to a significant reduction in plaque size, IP angiogenesis and hemorrhagic complications in a vein graft model. These findings suggest that endothelial glycolysis inhibition may represent a new therapeutic strategy to slow down plaque progression in vein grafts.A study performed in collaboration with the University of Aberdeen is also presented in this thesis. Here the development of a new PFKFB3-targeted PET radiotracer, [18F]ZCDD083, for in vivo plaque imaging is described. The specificity of the tracer for atherosclerotic plaques is demonstrated by a combination of ex vivo autoradiography and en face Oil Red O staining. This tracer is a promising non-invasive diagnostic tool to detect rupture-prone atherosclerotic plaques,Finally, a novel imaging method for a three-dimensional reconstruction of the IP vessel network is presented. This method is based on iDISCO immunolabeling and confocal microscopy. It may represent a novel tool to investigate the causal relationship between IP angiogenesis and atherogenesis.Overall, the experimental data generated in this thesis strongly argue for a critical role of EC metabolism in the formation and progression of atherosclerosis in addition to IP angiogenesis. Show less
Studies have shown that the quantitative flow ratio (QFR), recently introduced to assess lesion severity from coronary angiography, provides useful prognostic information; however the additive... Show moreStudies have shown that the quantitative flow ratio (QFR), recently introduced to assess lesion severity from coronary angiography, provides useful prognostic information; however the additive value of this technique over intravascular imaging in detecting lesions that are likely to cause events is yet unclear. We analysed data acquired in the PROSPECT and IBIS-4 studies, in particular the baseline virtual histology-intravascular ultrasound (VH-IVUS) and angiographic data from 17 non-culprit lesions with a presumable vulnerable phenotype (i.e., thin or thick cap fibroatheroma) that caused major adverse cardiac events or required revascularization (MACE) at 5-year follow-up and from a group of 78 vulnerable plaques that remained quiescent. The segments studied by VH-IVUS were identified in coronary angiography and the QFR was estimated. The additive value of 3-dimensional quantitative coronary angiography (3D-QCA) and of the QFR in predicting MACE at 5 year follow-up beyond plaque characteristics was examined. It was found that MACE lesions had a greater plaque burden (PB) and smaller minimum lumen area (MLA) on VH-IVUS, a longer length and a smaller minimum lumen diameter (MLD) on 3D-QCA and a lower QFR compared with lesions that remained quiescent. By univariate analysis MLA, PB, MLD, lesion length on 3D-QCA and QFR were predictors of MACE. In multivariate analysis a low but normal QFR (> 0.80 to < 0.97) was the only independent prediction of MACE (HR 3.53, 95% CI 1.16-10.75; P = 0.027). In non-flow limiting lesions with a vulnerable phenotype, QFR may provide additional prognostic information beyond plaque morphology for predicting MACE throughout 5 years. Show less
During the past few years CTA has rapidly developed into a versatile non-invasive imaging modality. While imaging of the coronary arteries to determine or rule out the presence of stenosis will... Show moreDuring the past few years CTA has rapidly developed into a versatile non-invasive imaging modality. While imaging of the coronary arteries to determine or rule out the presence of stenosis will remain one of the main indications, additional information on plaque severity and composition can be obtained. The improvements in technology (faster gantry rotation times, an increasing number of detectors, volumetric image acquisition) and consequential improvement in image quality have resulted in advances in the characterization of coronary atherosclerosis and vulnerable plaque. Interestingly, the diagnostic performance of CTA was superior in the evaluation of presence or absence of clinically relevant atherosclerosis as compared to the evaluation of signifi cant stenosis. Regarding plaque observations with the novel 320-row CTA scanner, the results showed good agreement to relative plaque composition on invasive VH IVUS. Moreover, mixed plaques on 320-row CTA paralleled the more vulnerable plaque on VH IVUS. In addition, lesions with spotty calcifi cations and positive remodeling on CTA were associated with a higher percentage necrotic core and a higher prevalence of vulnerable plaques. Accordingly, evaluation of spotty calcifi cations and remodeling on CTA may be valuable markers for plaque vulnerability. The relation between characterization of atherosclerosis on CTA and its effect on clinical management was also evaluated. As a result of rapid developments in coronary CTA technology, high diagnostic accuracies of 320-row CTA for detecting coronary stenosis were obtained in patients with stable chest pain complaints as well as in patients presenting with acute chest pain. In addition, although a zero calcium score has important prognostic value, patients with acute coronary syndrome and zero calcium had increased plaque burden as well as increased vulnerability as compared to patients with stable chest pain. Accordingly, absence of coronary calcifi cation did not exclude the presence of clinically relevant and potentially vulnerable atherosclerotic plaque burden in patients with acute coronary syndrome. Lastly, in addition to the degree of stenosis, CTA variables of atherosclerosis describing plaque extent, composition and location were predictive of the presence of ischemia on myocardial perfusion imaging. Possibly, these results may allow a more refi ned and individualized assessment of patients undergoing CTA imaging and provide the basis for the development of an algorithm to improve identifi cation of patients requiring more aggressive therapy or intervention. Show less
